tbuckley/cabot-search huggingface dataset:
Phase 2 Study of Aficamten in Patients With Obstructive Hypertrophic Cardiomyopathy
Authors: Martin S. Maron, Ahmad Masri, Lubna Choudhury, Iacopo Olivotto, Sara Saberi, Andrew Wang, Pablo Garcia-Pavia, Neal K. Lakdawala, Sherif F. Nagueh, Florian Rader, Albree Tower-Rader, Aslan T. Turer, Caroline Coats, Michael A. Fifer, Anjali Owens, Scott D. Solomon, Hugh Watkins, Roberto Barriales-Villa, Christopher M. Kramer, Timothy C. Wong, Sharon L. Paige, Stephen B. Heitner, Stuart Kupfer, Fady I. Malik, Lisa Meng, Amy Wohltman, Theodore Abraham
Journal: Journal of the American College of Cardiology (2023)

Left ventricular outflow tract (LVOT) obstruction is a major determinant of heart failure symptoms in obstructive hypertrophic cardiomyopathy (oHCM). Aficamten, a next-in-class cardiac myosin inhibitor, may lower gradients and improve symptoms in these patients.This study aims to evaluate the safety and efficacy of aficamten in patients with oHCM.Patients with oHCM and LVOT gradients ≥30 mm Hg at rest or ≥50 mm Hg with Valsalva were randomized 2:1 to receive aficamten (n = 28) or placebo (n = 13) in 2 dose-finding cohorts. Doses were titrated based on gradients and ejection fraction (EF). Safety and changes in gradient, EF, New York Heart Association functional class, and cardiac biomarkers were assessed over a 10-week treatment period and after a 2-week washout.From baseline to 10 weeks, aficamten reduced gradients at rest (mean difference: -40 ± 27 mm Hg, and -43 ± 37 mm Hg in Cohorts 1 and 2, P = 0.0003 and P = 0.0004 vs placebo, respectively) and with Valsalva (-36 ± 27 mm Hg and -53 ± 44 mm Hg, P = 0.001 and <0.0001 vs placebo, respectively). There were modest reductions in EF (-6% ± 7.5% and -12% ± 5.9%, P = 0.007 and P < 0.0001 vs placebo, respectively). Symptomatic improvement in ≥1 New York Heart Association functional class was observed in 31% on placebo, and 43% and 64% on aficamten in Cohorts 1 and 2, respectively (nonsignificant). With aficamten, N-terminal pro-B-type natriuretic peptide was reduced (62% relative to placebo, P = 0.0002). There were no treatment interruptions and adverse events were similar between treatment arms.Aficamten resulted in substantial reductions in LVOT gradients with most patients experiencing improvement in biomarkers and symptoms. These results highlight the potential of sarcomere-targeted therapy for treatment of oHCM.
Cell-type-specific aging clocks to quantify aging and rejuvenation in neurogenic regions of the brain
Authors: Matthew T. Buckley, Eric D. Sun, Benson M. George, Ling Liu, Nicholas Schaum, Lucy Xu, Jaime M. Reyes, Margaret A. Goodell, Irving L. Weissman, Tony Wyss-Coray, Thomas A. Rando, Anne Brunet
Journal: Nature Aging (2022)

Abstract The diversity of cell types is a challenge for quantifying aging and its reversal. Here we develop ‘aging clocks’ based on single-cell transcriptomics to characterize cell-type-specific aging and rejuvenation. We generated single-cell transcriptomes from the subventricular zone neurogenic region of 28 mice, tiling ages from young to old. We trained single-cell-based regression models to predict chronological age and biological age (neural stem cell proliferation capacity). These aging clocks are generalizable to independent cohorts of mice, other regions of the brains, and other species. To determine if these aging clocks could quantify transcriptomic rejuvenation, we generated single-cell transcriptomic datasets of neurogenic regions for two interventions—heterochronic parabiosis and exercise. Aging clocks revealed that heterochronic parabiosis and exercise reverse transcriptomic aging in neurogenic regions, but in different ways. This study represents the first development of high-resolution aging clocks from single-cell transcriptomic data and demonstrates their application to quantify transcriptomic rejuvenation.
Hematopoietic stem cell donor vaccination with cytomegalovirus triplex augments frequencies of functional and durable cytomegalovirus‐specific T cells in the recipient: A novel strategy to limit antiviral prophylaxis
Authors: Corinna La Rosa, Ibrahim Aldoss, Yoonsuh Park, Dongyun Yang, Qiao Zhou, Ketevan Gendzekhadze, Teodora Kaltcheva, Wasima Rida, Shannon Dempsey, Shukaib Arslan, Andrew Artz, Brian Ball, Liana Nikolaenko, Vinod A. Pullarkat, Ryotaro Nakamura, Don J. Diamond
Journal: American Journal of Hematology (2023)

To enhance protective cytomegalovirus (CMV)-specific T cells in immunosuppressed recipients of an allogeneic hematopoietic cell transplant (HCT), we evaluated post-HCT impact of vaccinating healthy HCT donors with Triplex. Triplex is a viral vectored recombinant vaccine expressing three immunodominant CMV antigens. The vector is modified vaccinia Ankara (MVA), an attenuated, non-replicating poxvirus derived from the vaccinia virus strain Ankara. It demonstrated tolerability and immunogenicity in healthy adults and HCT recipients, in whom it also reduced CMV reactivation. Here, we report feasibility, safety, and immunological outcomes of a pilot phase 1 trial (NCT03560752 at ClinicalTrials.gov) including 17 CMV-seropositive recipients who received an HCT from a matched related donor (MRD) vaccinated with 5.1 × 10
Imaging drug delivery to the lungs: Methods and applications in oncology
Authors: Francis Man, Jie Tang, Magda Swedrowska, Ben Forbes, Rafael T.M. de Rosales
Journal: Advanced Drug Delivery Reviews (2022)

Direct delivery to the lung via inhalation is arguably one of the most logical approaches to treat lung cancer using drugs. However, despite significant efforts and investment in this area, this strategy has not progressed in clinical trials. Imaging drug delivery is a powerful tool to understand and develop novel drug delivery strategies. In this review we focus on imaging studies of drug delivery by the inhalation route, to provide a broad overview of the field to date and attempt to better understand the complexities of this route of administration and the significant barriers that it faces, as well as its advantages. We start with a discussion of the specific challenges for drug delivery to the lung via inhalation. We focus on the barriers that have prevented progress of this approach in oncology, as well as the most recent developments in this area. This is followed by a comprehensive overview of the different imaging modalities that are relevant to lung drug delivery, including nuclear imaging, X-ray imaging, magnetic resonance imaging, optical imaging and mass spectrometry imaging. For each of these modalities, examples from the literature where these techniques have been explored are provided. Finally the different applications of these technologies in oncology are discussed, focusing separately on small molecules and nanomedicines. We hope that this comprehensive review will be informative to the field and will guide the future preclinical and clinical development of this promising drug delivery strategy to maximise its therapeutic potential.
Post-vaccine epidemiology of serotype 3 pneumococci identifies transformation inhibition through prophage-driven alteration of a non-coding RNA
Authors: Min Jung Kwun, Alexandru V. Ion, Hsueh-Chien Cheng, Joshua C. D’Aeth, Sam Dougan, Marco R. Oggioni, David A. Goulding, Stephen D. Bentley, Nicholas J. Croucher
Journal: Genome Medicine (2022)

Abstract Background The respiratory pathogen Streptococcus pneumoniae (the pneumococcus) is a genetically diverse bacterium associated with over 101 immunologically distinct polysaccharide capsules (serotypes). Polysaccharide conjugate vaccines (PCVs) have successfully eliminated multiple targeted serotypes, yet the mucoid serotype 3 has persisted despite its inclusion in PCV13. This capsule type is predominantly associated with a single globally disseminated strain, GPSC12 (clonal complex 180). Methods A genomic epidemiology study combined previous surveillance datasets of serotype 3 pneumococci to analyse the population structure, dynamics, and differences in rates of diversification within GPSC12 during the period of PCV introductions. Transcriptomic analyses, whole genome sequencing, mutagenesis, and electron microscopy were used to characterise the phenotypic impact of loci hypothesised to affect this strain’s evolution. Results GPSC12 was split into clades by a genomic analysis. Clade I, the most common, rarely underwent transformation, but was typically infected with the prophage ϕOXC141. Prior to the introduction of PCV13, this clade’s composition shifted towards a ϕOXC141-negative subpopulation in a systematically sampled UK collection. In the post-PCV13 era, more rapidly recombining non-Clade I isolates, also ϕOXC141-negative, have risen in prevalence. The low in vitro transformation efficiency of a Clade I isolate could not be fully explained by the ~100-fold reduction attributable to the serotype 3 capsule. Accordingly, prophage ϕOXC141 was found to modify csRNA3, a non-coding RNA that inhibits the induction of transformation. This alteration was identified in ~30% of all pneumococci and was particularly common in the unusually clonal serotype 1 GPSC2 strain. RNA-seq and quantitative reverse transcriptase PCR experiments using a genetically tractable pneumococcus demonstrated the altered csRNA3 was more effective at inhibiting production of the competence-stimulating peptide pheromone. This resulted in a reduction in the induction of competence for transformation. Conclusion This interference with the quorum sensing needed to induce competence reduces the risk of the prophage being deleted by homologous recombination. Hence the selfish prophage-driven alteration of a regulatory RNA limits cell-cell communication and horizontal gene transfer, complicating the interpretation of post-vaccine population dynamics.
Association between acute disease severity and one-year quality of life among post-hospitalisation COVID-19 patients: Coalition VII prospective cohort study
Authors: Regis Goulart Rosa, Alexandre Biasi Cavalcanti, Luciano César Pontes Azevedo, Viviane Cordeiro Veiga, Denise de Souza, Rosa da Rosa Minho dos Santos, Raíne Fogliati de Carli Schardosim, Gabriela Soares Rech, Geraldine Trott, Daniel Schneider, Caroline Cabral Robinson, Tainá Aparecida Haubert, Victoria Emanuele Lobo Pallaoro, Liége Gregoletto Brognoli, Ana Paula de Souza, Lauren Sezerá Costa, Bruna Machado Barroso, Melissa Pezzetti Pelliccioli, Janine Gonzaga, Nicole dos Santos Studier, Ana Paula Aquistapase Dagnino, Juliana de Mesquita Neto, Sabrina Souza da Silva, Bruna dos Passos Gimenes, Vanessa Brzoskowski dos Santos, Gabriel Pozza Muller Estivalete, Carolina de Moraes Pellegrino, Carisi Anne Polanczyk, Letícia Kawano-Dourado, Bruno Martins Tomazini, Thiago Costa Lisboa, Cassiano Teixeira, Fernando Godinho Zampieri, Alexandre Prehn Zavascki, Bernard J. Gersh, Álvaro Avezum, Flávia Ribeiro Machado, Otavio Berwanger, Renato Delascio Lopes, Maicon Falavigna
Journal: Intensive Care Medicine (2023)
Improved antitumor activity against prostate cancer via synergistic targeting of Myc and GFAT-1
Authors: Yue Zhang, Jiang Li, Yixian Huang, Yuang Chen, Zhangyi Luo, Haozhe Huang, Raymond E. West, Thomas D. Nolin, Zhou Wang, Song Li
Journal: Theranostics (2023)

Inhibition of Myc promotes the regression of many types of tumors, including prostate cancer. However, the success of anti-Myc therapy is hampered by the lack of a strategy to effectively deliver the inhibitors to the tumor site and by the feedback mechanisms that cancer cells use to adapt to metabolic reprogramming.
Hippo pathway activation mediates chemotherapy-induced anti-cancer effect and cardiomyopathy through causing mitochondrial damage and dysfunction
Authors: Gang She, Jin-Chan Du, Wei Wu, Tian-Tian Pu, Yu Zhang, Ru-Yue Bai, Yi Zhang, Zheng-Da Pang, Hui-Fang Wang, Yu-Jie Ren, Junichi Sadoshima, Xiu-Ling Deng, Xiao-Jun Du
Journal: Theranostics (2023)

Rationale: Chemotherapy is a common clinical strategy for cancer treatment.However, the accompanied cardiomyopathy renders cancer patients under risk of another life-threatening condition.Whereas Hippo pathway is known to play key roles in both cancerogenesis and heart disease, it remains unclear whether Hippo pathway activation mediates chemotherapy-induced cardiomyopathy.Methods and Results: In human breast cancer cells, doxorubicin (DOX) significantly induced upregulation of Hippo kinase Mst1, inhibitory phosphorylation of YAP, mitochondrial damage, reduced cell viability and increased apoptosis.Hippo pathway inactivation by Mst1-siRNA transfection effectively improved cell survival and mitigated mitochondrial damage and cell apoptosis.Another anti-cancer drug YAP inhibitor verteporfin also induced lower cancer cell viability, apoptosis and mitochondrial injury.Chronic treatment with DOX in vivo (4 mg/kg/week for 6 weeks) caused mitochondrial damage and dysfunction, oxidative stress and cardiac fibrosis, while acute DOX treatment (16 mg/kg single bolus) also induced myocardial oxidative stress and mitochondrial abnormalities.Chronic treatment with verteporfin (2 months) resulted in cardiomyopathy phenotypes comparable to that by chronic DOX regimen.In transgenic mice with cardiac overexpression of kinase-dead mutant Mst1 gene, these adverse cardiac effects of DOX were significantly attenuated relative to wild-type littermates.Conclusions: Anti-cancer action of both DOX and verteporfin is associated with Hippo pathway activation.Such action on cardiac Hippo pathway mediates mitochondrial damage and cardiomyopathy.
Enhancer RNA promotes resistance to radiotherapy in bone-metastatic prostate cancer by m<sup>6</sup>A modification
Authors: Yu Zhao, Simeng Wen, Hang Li, Chun-Wu Pan, Yulei Wei, Ting Huang, Zhaochen Li, Yinhui Yang, Saijun Fan, Yingyi Zhang
Journal: Theranostics (2023)

Rationale: Prostate cancer metastasizes to the bone with the highest frequency and exhibits high resistance to 177 Lu-prostate-specific membrane antigen (PSMA) radioligand therapy.Little is known about bone metastatic prostate cancer (mPCa) resistance to radiation.Methods: We filtered the metastatic eRNA using RNA-seq, MeRIP-seq, RT-qPCR and bioinformation.Western blot, RT-qPCR, CLIP, co-IP and RNA pull-down assays were used for RNA/protein interaction, RNA or protein expression examination.MTS assay was used to determine cell viability in vitro, xenograft assay was used to examine the tumor growth in mice.Results: In this study, we screened and identified bone-specific N6 adenosine methylation (m 6 A) on enhancer RNA (eRNA) that played a post-transcriptional functional role in bone mPCa and was correlated with radiotherapy (RT) resistance.Further data demonstrated that RNA-binding protein KHSRP recognized both m 6 A at eRNA and m 6 Am at 5'-UTR of mRNA to block RNA degradation from exoribonuclease XRN2.Depletion of the MLXIPe/KHSRP/PSMD9 regulatory complex inhibited tumor growth and RT sensitization of bone mPCa xenograft in vitro and in vivo.Conclusions: Our findings indicate that a bone-specific m 6 A-modified eRNA plays a vital role in regulating mPCa progression and RT resistance and might be a novel specific predictor for cancer RT.
FAM3C in circulating tumor-derived extracellular vesicles promotes non-small cell lung cancer growth in secondary sites
Authors: Win Lwin Thuya, Li Ren Kong, Nicholas L. Syn, Ling-Wen Ding, Esther Sok Hwee Cheow, Regina Tong Xin Wong, Tingting Wang, Robby Miguel Wen-Jing Goh, Hongyan Song, Migara K. Jayasinghe, Minh TN Le, Jian Cheng Hu, Wei-Peng Yong, Soo-Chin Lee, Andrea Li-Ann Wong, Gautam Sethi, Huynh The Hung, Paul Chi-Lui Ho, Jean-Paul Thiery, Siu Kwan Sze, Tiannan Guo, Ross A. Soo, Henry Yang, Yaw Chyn Lim, Lingzhi Wang, Boon-Cher Goh
Journal: Theranostics (2023)

Rationale: Metastasis is a complex process with a molecular underpinning that remains unclear.We hypothesize that cargo proteins conducted by extracellular vesicles (EVs) released from tumors may confer growth and metastasis potential on recipient cells.Here, we report that a cytokine-like secreted protein, FAM3C, contributes to late-stage lung tumor progression.Methods: EV protein profiling was conducted with an unbiased proteomic mass spectrometry analysis on non-small cell lung cancer (NSCLC) and normal lung fibroblast cell lines.Expression of FAM3C was confirmed in a panel of NSCLC cell lines, and correlated to the invasive and metastatic potentials.Functional phenotype of endogenous FAM3C and tumor-derived EVs (TDEs) were further investigated using various biological approaches in RNA and protein levels.Metastasis potential of TDEs secreted by FAM3C-overexpressing carcinoma cells was validated in mouse models.Results: Transcriptomic meta-analysis of pan-cancer datasets confirmed the overexpression of FAM3C -a gene encoding for interleukin-like EMT inducer (ILEI) -in NSCLC tumors, with strong association with poor patient prognosis and cancer metastasis.Aberrant expression of FAM3C in lung carcinoma cells enhances cellular transformation and promotes distant lung tumor colonization.In addition, higher FAM3C concentrations were detected in EVs extracted from plasma samples of NSCLC patients compared to those of healthy subjects.More importantly, we defined a hitherto-unknown mode of microenvironmental crosstalk involving FAM3C in EVs, whereby the delivery and uptake of FAM3C via TDEs enhances oncogenic signaling -in recipient cells that phenocopies the cell-endogenous overexpression of FAM3C.The oncogenicity transduced by FAM3C is executed via a novel interaction with the Ras-related protein RalA, triggering the downstream activation of the Src/Stat3 signaling cascade.
Combined thioredoxin reductase and glutaminase inhibition exerts synergistic anti-tumor activity in MYC-high high-grade serous ovarian carcinoma
Authors: Prahlad V. Raninga, Yaowu He, Keshava K. Datta, Xue Lu, Uma R. Maheshwari, Pooja Venkat, Chelsea Mayoh, Harsha Gowda, Murugan Kalimutho, John D. Hooper, Kum Kum Khanna
Journal: Molecular Therapy (2022)

Approximately 50%–55% of high-grade serous ovarian carcinoma (HGSOC) patients have MYC oncogenic pathway activation. Because MYC is not directly targetable, we have analyzed molecular pathways enriched in MYC-high HGSOC tumors to identify potential therapeutic targets. Here, we report that MYC-high HGSOC tumors show enrichment in genes controlled by NRF2, an antioxidant signaling pathway, along with increased thioredoxin redox activity. Treatment of MYC-high HGSOC tumors cells with US Food and Drug Administration (FDA)-approved thioredoxin reductase 1 (TrxR1) inhibitor auranofin resulted in significant growth suppression and apoptosis in MYC-high HGSOC cells in vitro and also significantly reduced tumor growth in an MYC-high HGSOC patient-derived tumor xenograft. We found that auranofin treatment inhibited glycolysis in MYC-high cells via oxidation-induced GAPDH inhibition. Interestingly, in response to auranofin-induced glycolysis inhibition, MYC-high HGSOC cells switched to glutamine metabolism for survival. Depletion of glutamine with either glutamine starvation or glutaminase (GLS1) inhibitor CB-839 exerted synergistic anti-tumor activity with auranofin in HGSOC cells and OVCAR-8 cell line xenograft. These findings suggest that applying a combined therapy of GLS1 inhibitor and TrxR1 inhibitor could effectively treat MYC-high HGSOC patients. Approximately 50%–55% of high-grade serous ovarian carcinoma (HGSOC) patients have MYC oncogenic pathway activation. Because MYC is not directly targetable, we have analyzed molecular pathways enriched in MYC-high HGSOC tumors to identify potential therapeutic targets. Here, we report that MYC-high HGSOC tumors show enrichment in genes controlled by NRF2, an antioxidant signaling pathway, along with increased thioredoxin redox activity. Treatment of MYC-high HGSOC tumors cells with US Food and Drug Administration (FDA)-approved thioredoxin reductase 1 (TrxR1) inhibitor auranofin resulted in significant growth suppression and apoptosis in MYC-high HGSOC cells in vitro and also significantly reduced tumor growth in an MYC-high HGSOC patient-derived tumor xenograft. We found that auranofin treatment inhibited glycolysis in MYC-high cells via oxidation-induced GAPDH inhibition. Interestingly, in response to auranofin-induced glycolysis inhibition, MYC-high HGSOC cells switched to glutamine metabolism for survival. Depletion of glutamine with either glutamine starvation or glutaminase (GLS1) inhibitor CB-839 exerted synergistic anti-tumor activity with auranofin in HGSOC cells and OVCAR-8 cell line xenograft. These findings suggest that applying a combined therapy of GLS1 inhibitor and TrxR1 inhibitor could effectively treat MYC-high HGSOC patients.
Neutralizing antibodies against Omicron BA.4/5 after COVID-19 vaccination in SARS-CoV-2 experienced versus naïve individuals in the general population
Authors: Jorge Camacho, Joao Zulaica, Estela Giménez, Luciana Rusu, Sebastian Velandia-Álvarez, Eliseo Albert, Salvador Peiró, Hermelinda Vanaclocha, Ramón Limón, Ron Geller, David Navarro
Journal: Journal of Infection (2023)
Junior doctors are cutting back on food and heating amid cost of living crisis, BMA poll finds
Authors: Adele Waters
Journal: BMJ (2022)

Junior doctors are cutting back on food and heating amid cost of living crisis, BMA poll finds Adele WatersThe effects of the cost of living crisis in the UK have been brought into sharp focus with results from a BMA survey that has shown that junior doctors are having to cut back on food and heating their homes and are even regularly borrowing money from family and friends.
The effect of parental leave on parents’ mental health: a systematic review
Authors: Amy Heshmati, Helena Honkaniemi, Sol P Juárez
Journal: The Lancet Public Health (2023)

Mental health disorders during the post-partum period are a common morbidity, but parental leave might help alleviate symptoms by preventing or reducing stress. We aim to summarise available evidence on the effect of different types of parental leave on mental health outcomes among parents. For this systematic review, we searched Ovid MEDLINE, Web of Science, PsycINFO, CINAHL, and Scopus from database inception to Aug 29, 2022, for peer-reviewed, quantitative studies written in English. We included studies if the exposure was postnatal parental leave; a relevant comparison group was present (eg, paid vs unpaid leave); and if indicators related to general mental health, including depression, anxiety, stress, and suicide, for either parent were evaluated or recorded at any time after childbirth. The Review is registered with PROSPERO (registration number CRD42021227499). Of the 3441 records screened, 45 studies were narratively synthesised. Studies were done in high-income countries, and they examined generosity by any parental leave (n=5), benefit amount (n=13), and leave duration (n=31). 38 studies were of medium or high quality. Improved mental health was generally observed among women (referred to as mothers in this Review) with more generous parental leave policies (ie, leave duration and paid vs unpaid leave). For example, increased duration of leave was generally associated with reduced risk of poor maternal mental health, including depressive symptoms, psychological distress and burnout, and lower mental health-care uptake. However, the association between fathers' leave and paternal mental health outcomes was less conclusive as was the indirect effect of parental leave use on partners' mental health.
Health and cancer risks associated with low levels of alcohol consumption
Authors: Benjamin O Anderson, Nino Berdzuli, Andre Ilbawi, Dévora Kestel, Hans P Kluge, Rüdiger Krech, Bente Mikkelsen, Maria Neufeld, Vladimir Poznyak, Dag Rekve, Slim Slama, Juan Tello, Carina Ferreira-Borges
Journal: The Lancet Public Health (2023)
Heavy prenatal alcohol exposure and obstetric and birth outcomes: a Danish nationwide cohort study from 1996 to 2018
Authors: Marcella Broccia, Bo Mølholm Hansen, Julie Marie Winckler, Thomas Larsen, Katrine Strandberg-Larsen, Christian Torp-Pedersen, Ulrik Schiøler Kesmodel
Journal: The Lancet Public Health (2023)